Pax6 Is Required at the Telencephalic Pallial-Subpallial Boundary for the Generation of Neuronal Diversity in the Postnatal Limbic System

Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC 20010, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 04/2011; 31(14):5313-24. DOI: 10.1523/JNEUROSCI.3867-10.2011
Source: PubMed


During embryogenesis, the pallial-subpallial boundary (PSB) divides the two main progenitor domains in the telencephalon: the pallium, the major source of excitatory neurons, and the subpallium, the major source of inhibitory neurons. The PSB is formed at the molecular interface between the pallial (high Pax6+) and subpallial (high Gsx2+) ventricular zone (VZ) compartments. Initially, the PSB contains cells that express both Pax6 and Gsx2, but during later stages of development this boundary is largely refined into two separate compartments. In this study we examined the developmental mechanisms underlying PSB boundary formation and the postnatal consequences of conditional loss of Pax6 function at the PSB on neuronal fate in the amygdala and olfactory bulb, two targets of PSB-derived migratory populations. Our cell fate and time-lapse imaging analyses reveal that the sorting of Pax6+ and Gsx2+ progenitors during embryogenesis is the result of a combination of changes in gene expression and cell movements. Interestingly, we find that in addition to giving rise to inhibitory neurons in the amygdala and olfactory bulb, Gsx2+ progenitors generate a subpopulation of amygdala excitatory neurons. Consistent with this finding, targeted conditional ablation of Pax6 in Gsx2+ progenitors results in discrete local embryonic patterning defects that are linked to changes in the generation of subsets of postnatal excitatory and inhibitory neurons in the amygdala and inhibitory neurons in the olfactory bulb. Thus, in PSB progenitors, Pax6 plays an important role in the generation of multiple subtypes of neurons that contribute to the amygdala and olfactory bulb.

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Available from: Nicoletta Kessaris, Oct 05, 2015
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    • "Furthermore , Pax6 specifies the antihem, which is coextensive with the ventral pallium and secretes EGFs, FGFs and frizzled-related proteins (FRPs) that counteract the influence of dorsal signals like Wnts (Assimacopoulos et al., 2003). Pax6 and the antihem participate in the differentiation of pallial amygdalar structures (Cocas et al., 2011), and Pax6 is required for proper development of both ventral and dorsal pallial structures in mammals (for more detailed reviews involving these and additional regulatory systems see Hoch et al., 2009; Medina and Abellán, 2009; Medina et al., 2011, and Alfano and Studer, 2013). "
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    ABSTRACT: The anatomical organization of the mammalian neocortex stands out among vertebrates for its laminar and columnar arrangement, featuring vertically oriented, excitatory pyramidal neurons. The evolutionary origin of this structure is discussed here in relation to the brain organization of other amniotes, i.e., the sauropsids (reptiles and birds). Specifically, we address the developmental modifications that had to take place to generate the neocortex, and to what extent these modifications were shared by other amniote lineages or can be considered unique to mammals. In this article, we propose a hypothesis that combines the control of proliferation in neural progenitor pools with the specification of regional morphogenetic gradients, yielding different anatomical results by virtue of the differential modulation of these processes in each lineage. Thus, there is a highly conserved genetic and developmental battery that becomes modulated in different directions according to specific selective pressures. In the case of early mammals, ecological conditions like nocturnal habits and reproductive strategies are considered to have played a key role in the selection of the particular brain patterning mechanisms that led to the origin of the neocortex.
    Frontiers in Neuroanatomy 11/2013; 7:38. DOI:10.3389/fnana.2013.00038 · 3.54 Impact Factor
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    • "The migratory cells of the lateral cortical stream (LCS) are derived from progenitors in the VZ of the PSPB and migrate ventrally towards the amygdaloid region where they contribute to the developing amygdala [47,50,59,60]. The LCS contains cells derived from both the pallium (Pax6+ and Tbr1+) and the subpallium (Dlx2+ and Gsh2+) [47,50,59]. Tau-GFP labels a set of Pax6-expressing cells which appear to be migrating towards the basolateral telencephalon of our PAX6 YAC transgenic lines at both E12.5 and E15.5. "
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    ABSTRACT: The transcription factor Pax6 is a crucial regulator of eye and central nervous system development. Both the spatiotemporal patterns and the precise levels of Pax6 expression are subject to tight control, mediated by an extensive set of cis-regulatory elements. Previous studies have shown that a YAC reporter transgene containing 420Kb of genomic DNA spanning the human PAX6 locus drives expression of a tau-tagged GFP reporter in mice in a pattern that closely resembles that of endogenous Pax6. Here we have closely compared the pattern of tau-GFP reporter expression at the cellular level in the forebrains and eyes of transgenic mice carrying either complete or truncated versions of the YAC reporter transgene with endogenous Pax6 expression and found several areas where expression of tau-GFP and Pax6 diverge. Some discrepancies are due to differences between the intracellular localization or perdurance of tau-GFP and Pax6 proteins, while others are likely to be a consequence of transcriptional differences. We show that cis-regulatory elements that lie outside the 420kb fragment of PAX6 are required for correct expression around the pallial-subpallial boundary, in the amygdala and the prethalamus. Further, we found that the YAC reporter transgene effectively labels cells that contribute to the lateral cortical stream, including cells that arise from the pallium and subpallium, and therefore represents a useful tool for studying lateral cortical stream migration.
    PLoS ONE 11/2013; 8(11):e80208. DOI:10.1371/journal.pone.0080208 · 3.23 Impact Factor
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    • "With regard to the amygdala, extensive work has revealed that neuronal cell diversity is generated from two sets of progenitor pools: those that contribute neurons to multiple telencephalic structures (e.g., cerebral cortex, hippocampus) and those that are unique to the amygdala. The shared sources include aspects of the cerebral cortex, the ventrally located telencephalic ganglionic eminences [medial (MGE), lateral (LGE) and caudal (CGE)], as well as diencephalic sources (Nery et al., 2002; Remedios et al., 2007; García-Moreno et al., 2010; Bupesh et al., 2011; Cocas et al., 2011) (see Figure 4). Progenitor pools located within each of these domains express combinations of the homedomain and bHLH containing genes, Lhx6, Nkx2.1, Gsx2, Mash1, and Ngn2, just to name a few. "
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    Frontiers in Molecular Neuroscience 04/2012; 5:55. DOI:10.3389/fnmol.2012.00055 · 4.08 Impact Factor
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